Ctbp1 And Metabolic Syndrome Induce Breast Cancer Progression And Lung Metastasis

Breast cancer (BrCa) is one of the most important public health problems in the entire world. Metabolic syndrome (MeS) increases the incidence and aggressiveness of BrCa. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. Recently, we generated a MeS-like experimental mice model by chronically feeding animals with high fat diet (HFD) and we found that CtBP1 and MeS modulated breast carcinogenesis and tumor growth. We also showed that CtBP1 and MeS decreased BrCa cell adhesion, a crucial event in the beginning of metastasis. Considering metastasis is still the main cause of death, and around 30 % of women with BrCa diagnosed at early stages will progress to metastatic stage, it is crucial to understand the impact of non-inherited factors and the mechanism underlying this process. The aim of this work was to explore CtBP1 and MeS role in BrCa cell migration and metastasis. By wound healing assay, we found that CtBP1 increased cell migration of MDA-MB-231 and 4T1 BrCa cells. To study CtBP1 and MeS effect in tumor progression, MeS nude mice induced by chronically feeding animals with HFD; and control diet fed animals, were injected with CtBP1-depleted expression or -control MDA-MB-231 cells. Six weeks post-injection primary tumors were surgically removed. After two weeks, mice were sacrificed and the presence of metastasis in lung, liver and ascites was analyzed by histology and/or quantified by RT-qPCR using specific primers for human GAPDH. Consistently with the onset of metastasis, MeS increased the number of mice that developed neoplastic ascites (20% in MeS vs. 50% in control) with presence of tumor cells (TC) detected by RT-qPCR. In addition, histological analysis and RT-qPCR quantitation revealed that CtBP1 hyperactivation by MeS significantly increased BrCa lung metastasis. Interestingly, human Vimentin mRNA was induced in TC from ascites compared to primary TC; while it was diminished in lung, suggesting the crucial role of EMT/MET processes in metastasis. Finally, we analyzed expression of cell adhesion and EMT-related genes in primary tumor tissue by RT-qPCR. We found that CtBP1 and MeS modulated cell adhesion and EMT expression genes: Vimentin, Slug, ITGB4, ITGB6, Col17A, FABP4 and PRSS2. Altogether, these results suggest a key role for MeS and CtBP1 inducing BrCa EMT and metastasis. Citation Format: Paula Lucia Farre, Georgina Scalise, Nicolas Guillermo Dalton, Rocio Belen Duca, Karen Daniela Grana, Cintia Massillo, Juliana Porretti, Adriana De Siervi, Paola De Luca. CtBP1 and metabolic syndrome induce breast cancer progression and lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1984. doi:10.1158/1538-7445.AM2017-1984